I have been devoted and aiming to establish an independent and innovative research program in epithelial stem cell biology and to study skin-related diseases. The K01 mentored research scientist development award will present great opportunities for me to acquire additional skills and expertise that are essential for my transitio into an independent position. As a postdoctoral fellow in the laboratory of Dr. Elaine Fuchs at The Rockefeller University, I find myself in a premium scientific environment that fully supports my career development and provides all the equipments, resources, facilities, and trainings that are necessary for me to complete this proposed work successfully and to transition into an independent faculty position. Eccrine sweat glands are widely distributed in most areas of human skin, and its proper maintenance and functioning is crucial for optimal thermoregulation and water balance throughout our lifetime. Patients born with Hypohidrotic (Anhydrotic) Ectodermal Dysplasia (HED) have defects in sweat gland development and suffer from constant high fever due to inability to dissipate heat efficiently, and their lives are at risk. The long-tem objective of this proposed research is to understand the molecular mechanisms in sweat gland development, more specifically, the epithelial-mesenchymal signaling crosstalk that are involved. Knowledge acquired from this proposed research will contribute to future sweat gland regeneration that may benefit patients with sweat gland deficiency. Previous studies on Human HED patients revealed that mutations in WNT10a, in addition to components in EDA pathways, cause defective sweat gland development. As EDA pathway has been well characterized to be indispensable for initiation of various ectodermal appendages, the role of Wnt signaling in the context of sweat gland development is unknown. In addition, epithelial-mesenchymal signaling crosstalk has been shown to dictate epithelial cell fate, but exact signaling components that are involved remain elusive. Based on prior knowledge, I hypothesize that Wnt signaling triggers changes in the expression of secreting factors from mesenchyme, which then in turn determine the cell fate of epithelial progenitors to derive sweat glands. Specifically in this research proposal, I plan to: 1) Characterize the temporal and spatial activities of Wnt signaling during sweat gland initiation and morphogenesis; 2) Identify mesenchymal signals that specify sweat gland cell fate and support glandular differentiation; 3) Determine whether BMP-Shh antagonism occurs in the context of sweat gland development. With the support of a K01 award, I will obtain the necessary training and techniques essential for my transition into an independent research position, and expand my expertise and capability to perform research of high quality. I will also develop additional skills on networking, management, and mentoring, which together will equip me to achieve my future research goals as an independent investigator.